Clostridium difficile infection ( CDI ) in children ( <16 years of age )

Publication: 08/09/2016  
Last review: 01/01/1900  
Next review: 01/09/2019  
Clinical Guideline
CURRENT 
ID: 4731 
Approved By: Improving Antimicrobial Prescribing Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2016  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Diagnosis and management of Clostridium difficile infection (CDI) in Children (<16 years of age)

Summary
Clostridium difficile infection ( CDI ) in children ( <16 years of age )

Summary of Guideline

This guideline outlines the management of proven Clostridium difficile infection in paediatric patients (2-16 years old) and including immunosuppressed individuals.

The guideline applies to children who have diarrhoea (type 5-7 stool, Bristol stool chart) and a positive Clostridium difficile infection result (a positive result for CDI requires both positive glutamate dehydrogenase (GDH) and positive toxin assays).

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Background

Clostridium difficile is a spore-forming, obligate anaerobic, Gram-positive bacillus and is acquired from the environment or by the faecal-oral route. Some strains produce toxins A and B which are responsible for intestinal disease. C. difficile is a cause of antimicrobial-associated diarrhoea and is a common health care-associated pathogen.

Clinical symptoms vary widely, from asymptomatic colonization, through mild diarrhoeal illness to pseudomembranous colitis with bloody diarrhoea, fever, and severe abdominal pain. Poor outcomes (intensive care admission, colectomy or death) do occur in children with CDI but these are uncommon, occurring in 2% in a recent Canadian series.1 Healthy neonates are frequently colonised by C. difficile and these strains may produce toxin without it causing disease. In a study of community samples in Oxfordshire colonisation rates in asymptomatic children under 30 months were approximately 20%.2

Presumed factors that increase the risk of acquiring CDI in children:3

  • Prolonged hospitalization
  • Antibiotic therapy or chemotherapy.
  • Multiple antibiotics.
  • Use of proton pump inhibitors.
  • Repeated enemas.
  • Use of nappies.
  • Prolonged nasogastric tube insertion, gastrostomy and jejunostomy tubes.
  • Underlying bowel disease, and renal insufficiency.
  • Gastrointestinal tract surgery
  • Impaired humeral immunity.

Infection is a major infection control hazard and Trust guidelines regarding this should be followed; see Source Isolation and Hand Hygiene Techniques for more details.

CDI usually requires specific treatment to reduce the duration of symptoms and the risk of spread (see Empirical antimicrobial therapy).

Infection control recommendations can be found at Clostridium difficile Infection Control Policy

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Clinical Diagnosis

Recommendation: Symptoms or clinical signs cannot be used to reliably distinguish CDI from other causes of diarrhoea in children.[Evidence level B]

Recommendation: CDI is diagnosis that requires either laboratory confirmation or visualization of pseudomembranes on sigmoidoscopy or colonoscopy. [Evidence level B]

Recommendation: This guideline applies to children 2-16 years old with diarrhoea (at least one type 5-7 stool, Bristol stool chart) and a positive CDI result (both positive glutamate dehydrogenase (GDH) and positive toxin assays)

Recommendation: Avoid routine testing for CDI in children younger than 2 years (carrier state rate is highest in this age group) and consider other causes of diarrhoea, particularly viruses.
[Evidence level B]

Evidence review/justification
Testing for CDI can be considered in children older than 2 years of age as the rate of asymptomatic colonisation drops children over 2, although it remains higher than that of adults, so ruling out other causes of gastrointestinal infections is essential.[2-7]

Endoscopic findings of pseudomembranes and hyperaemic, friable rectal mucosa suggest pseudomembranous colitis and are sufficient to diagnose CDI at any age.

For reference, Table 1 summarises the interpretation of Clostridium difficile laboratory test results.

Table 1. Clinical interpretation of Clostridium difficile laboratory test results.

Test result

Interpretation

GDH negative

No C. difficile infection or colonisation.

GDH positive / Cytotoxin negative

Potential C. difficile excretor.
C. difficile treatment not usually required.

GDH positive / Cytotoxin positive

C. difficile infection probable.
Treatment usually required.

Please see detail.aspx?id=677 to guide when testing is recommended.

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Severity Assessment

Recommendation: All CDI episodes should have the severity assessed and recorded daily in the medical notes (and the initial severity also recorded on the prescription chart.) [Evidence level D]

Table 1: Revised criteria for severity of Clostridium difficile infection in children.8

Criteria

Points

Diarrhoea >5 times a day

1

Abdominal pain and discomfort

1

Rising white cell count

1

Raised C-reactive protein

1

Pyrexia >38°C

1

Evidence of pseudomembranous colitis

2

Intensive care unit requirement

2

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Total score:

1–2=mild disease.
3–4=moderate disease.
≥5=severe disease.

Recommendation: Measure serum lactate daily in severe infection, until there are clinical signs of improvement or surgical intervention is required. [Evidence level D]

Evidence review/justification.
The severity assessment used here is a proposed adaptation of DH recommendations and has not been prospectively evaluated. It reliability will therefore be assessed 6 months after introduction of the guideline.

Only adult data support the recommendation for lactate measurement. In a retrospective analysis of adult intensive care unit admissions, patients with a serum lactate 5 mmol/L had an increased risk of dying (Adjusted Odds Ratio, 12.4; 95% CI, 2.4-63.7), whereas those with lactate between 2.2 and 4.9 mmol/L appeared to benefit from colectomy.9 As in other causes of severe sepsis, serum lactate can be a useful marker of deterioration requiring surgical assessment. DOH guidelines recommend monitoring lactate in life-threatening infection10, but it may be too late at this point; hence the recommendation for earlier testing.

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Investigation

Clinical
Recommendation: Patients with confirmed CDI should be assessed daily for severity of infection (see Table 2) including signs and symptoms of colitis.3,8,10 [Evidence level B]

Recommendation: Patients with confirmed CDI should have the frequency and severity of diarrhoea assessed and documented until resolution, using the Bristol Stool Chart.3,10 [Evidence level B]

Patients with C. difficile infection often have diarrhoea, which is profuse, watery and may have a characteristic smell, although none of these clinical features are specific for C. difficile infection and a microbiological diagnosis is required for confirmation.

Microbiological
Recommendation: Do not retest C. difficile toxin positive cases if patients are still symptomatic within a period of 28 days unless symptoms resolve and then recur and there is a need to confirm recurrent CDI.3,10 [Evidence level B]

Imaging
Recommendation: In suspected cases of ‘silent’ CDI, such as ileus, toxic megacolon or pseudomembranous colitis without diarrhoea, request abdominal imaging e.g. abdominal x-ray, CT scanning or abdominal US. [Evidence level B]

Blood tests
Recommendation: Send Full blood count, C-reactive protein and Urea and electrolytes in all cases.8
[Evidence level D]
Particular attention should be given to serum potassium levels, as large losses may occur in diarrhoeal faeces.

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Treatment
Non-Antimicrobial Treatment

NB Infection control recommendations can be found @ Clostridium difficile Infection Control Policy

Recommendation: Children with CDI should be reviewed daily and agreed plans regarding fluid resuscitation, electrolyte replacement and nutrition should be clearly documented in the patient’s notes.10,3 [Evidence level B]

Recommendation: The need for antimicrobials for other indications,7,10 proton pump inhibitors (PPI) and any medicines that can produce diarrhoea should be reviewed (Do not stop PPI where there is a history of gastrointestinal bleeds). [Evidence level B]

Recommendation: Severe CDI or patients with evidence of severe colitis (e.g. guarding, bloody diarrhoea, abdominal tenderness or radiological evidence) require specialist surgical input. Colectomy is required in some patients with megacolon, perforation or septic shock.9,11 [Evidence level B]

Recommendation: In severe infections that are not responding to antimicrobial regimens, intravenous immunoglobulin may be considered in consultation with an infection specialist. Approval of the immunoglobulin will be required (see DTC web pages). [Evidence level B]

Specialist Consultations
If symptoms fail to improve or worsen despite following this guideline, consult with microbiology or infectious diseases and gastroenterology as clinically indicated.

NB. Concurrent antimicrobial therapy is associated with lower cure rates, hence the need to review all antimicrobial prescriptions and stop them whenever possible.3,7,10

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Empirical Antimicrobial Treatment

While this guideline relates primarily to confirmed cases of CDI, if there is a strong clinical suspicion of severe CDI infection, it is clinically sensible to begin therapy empirically (see below) pending test results.

For those with suspected moderate disease but potential recurrence, it is a clinical decision if to commence therapy empirically (see below), pending test results.

For those suspected of mild disease only, it would usually be appropriate to withhold treatment pending test results.

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Directed Antimicrobial Treatment (when microbiology results are known)

Recommendation: In all cases the need for (non-CDI) antimicrobials should be reviewed as these are associated with poorer outcome. [Evidence level B]

Recommendation: Risk stratify treatment choices by severity of illness [Evidence level C]

Recommendations:
Mild disease. No need to treat if symptoms are already settling at the time of CDI confirmation, or by the next morning ward review. If treatment is needed, use regimen for moderate disease.

Moderate disease. Metronidazole (Child 1–2 months 7.5 mg/kg every 12 hours, Child 2 months–12 years 7.5 mg/kg (max. 400 mg) every 8 hours,

Child 12–18 years 400 mg every 8 hours, for 10 days : BNFc) or oral vancomycin (Child 1 month–5 years 5 mg/kg 4 times daily for 10 days, Child 5–12 years 62.5 mg 4 times daily for 10 days, Child 12–18 years 125 mg 4 times daily: BNFc ) if no resolution of symptoms or deterioration in severity score. For patients unable to take oral therapy, the IV route can be used, but appears less effective.

Severe disease. Use oral vancomycin (Child 1 month–5 years 5 mg/kg 4 times daily, increased up to 10 mg/kg 4 times daily if infection fails to respond or is life-threatening; Child 5–12 years 62.5 mg 4 times daily, increased up to 250 mg 4 times daily if infection fails to respond or is life-threatening; Child 12–18 years 125 mg 4 times daily, increased up to 500 mg 4 times daily if infection fails to respond or is life-threatening: BNFc) and IV metronidazole, doses as above.

Evidence review
There is a limited evidence-base for treatment of CDI in children so these recommendations are extrapolated from adult recommendations, where there is now clear evidence that oral Metronidazole is inferior to vancomycin. Please see treatment failure section for more detailed review.

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Switch to oral agent(s)

This section is rarely relevant to CDI but in children with severe CDI who are commenced on IV Metronidazole , there is no need to change this to oral metronidazole, it can simply be stopped when there is clinical improvement.
[Evidence level D]

Duration of therapy
Recommendation: CDI treatment should be reviewed at day 10, if diarrhoea has resolved, treatment can be stopped; if diarrhoea is resolving complete 14 days therapy and stop.
[Evidence level D]

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Treatment Failure

Recommendation: Diarrhoea should resolve within 1-2 weeks, if diarrhoea has improved but persists at 14 days but the patient is otherwise stable, the WCC is normal, and there is no abdominal pain or distension, the persistent diarrhoea may be not due to infectious cause. [Evidence level D]

Recommendation: Treatment failure should not be assessed before day 7 of therapy [10]. [Evidence level C]

Recommendation: Seek a surgical opinion if symptoms worsen, severity score moves from moderate to severe or serum lactate worsens. [Evidence level C]

Recommendation: Recurrence of CDI is usually defined as recurrence of diarrhoea (at least 3 consecutive type 5-7 stools) and a positive C. difficile toxin assay within 30 days of a previous CDI episode and after resolution of previous symptoms (i.e. no diarrhoea for at least 48 hours).3,16
NB. Patients with previous CDI who do not fulfil criteria for a recurrence should be treated as a new episode of CDI, according to this guideline.

Recommendation: For first recurrent infection use Oral Vancomycin (40 mg/kg/day in 4 divided doses; maximum, 2 g/day). [Evidence level D]

For multiple recurrences/intractable cases, please see below.

Evidence review/justification.
Vancomycin and Metronidazole are long established therapies for CDI but both are associated with treatment failures and relapses.3,10 Data underlying therapies in children is generally weaker than that in adults, and extrapolation is challenging because of greater uncertainty about the natural history of the condition; children appear to have a mild course of disease despite having an acute response physiologically to infection.

Vancomycin and Metronidazole have similar efficacy for mild CDI, and in children, it was safe to use Metronidazole for moderate infection.8 Vancomycin appears to be superior for more severe infections.12-14 Because of concerns about cost and selection for Vancomycin resistant bacteria (e.g. vancomycin resistant enterococci, particularly in paediatric oncology patients) and a lack of superiority of Vancomycin for mild infection, Metronidazole is the recommended first line agent in this situation.3,5,7,8 Oral therapy is generally preferred to intravenous therapy because the pathogen, and thus the source of toxin production, is located in the bowel lumen; however, intravenous Metronidazole also reached bactericidal concentrations in faeces.15 There is no robust evidence that higher doses of Vancomycin (e.g. up to 2g/day) are more efficacious than lower doses in severe infection in adults, and standard 125mg dosing provides more than adequate stool concentrations), hence the dosing recommendation for severe infection. However, if there is evidence of ileus then, in severe infection, an increased dosage of oral vancomyin (up to 500mg four times daily) may be prudent. Intravenous therapy is advised in addition to oral/ng therapy in severe infection because impaired gut motility may slow/impair delivery of the antimicrobials to the site of infection.

The management of intractable cases and multiple recurrences is challenging and consultation with individuals experienced in managing these cases is advised. Investigational agents have been used with varying degrees of success

Beyond the use of Metronidazole and vancomycin as above, other therapies should only be considered on a case-by-case basis and in consultation with an infection specialist (microbiology or infectious diseases).

Recurrence

First recurrence
• The regimens used to treat patients with first episodes of C difficile associated colitis can be repeated for the first recurrence.

Second or later recurrences
• Second or later recurrences should typically be treated with vancomycin, using a higher dose (up to 2 gm/day) or using a tapered and/or pulsed regimen after discussion with specialist in microbiology/ infectious diseases.

An acceptable tapered regimen is as follows:

  • 40 mg/kg/day in four divided doses for 10 to 14 days (10 mg/kg per dose, maximum 125 mg/kg per dose); then
  • 10 mg/kg per dose twice per day for one week; then
  • 10 mg/kg per dose once per day for one week; and finally,
  • 10 mg/kg per dose every two or three days for two to eight weeks.

Evidence review/justification
Recurrent CDI can be a debilitating and costly problem but the majority of recurrences are re-infections as opposed to relapses.3,16 Recurrence occurs in 15-30% of cases after a first episode3 but higher after a second episode (30-60% in adults.17 Complication rates and further recurrences are higher after an initial relapse and prevention is therefore important.

Intravenous immunoglobulin may be appropriate (in consultation with microbiology/infectious diseases and the immunoglobulin review panel) in cases of recurrence in patients with low/deteriorating serum albumin.18 Tapering doses of Vancomycin have been used to treat CDI recurrence and remain an option but the regimens have not been standardized or fully evaluated.3

Donor stool transplants (Faecal microbiota transplantation) are occasionally required but this is an area requiring specialist input.

Fidaxomicin has been used in adults with CDI with comparable cure rates and some evidence of reduced recurrence rates in two randomised trials, overviewed by the NICE appraisals group.16 The use of this agent in children is based on one case report19 and a small safety evaluation and pharmacokinetic study20 and cannot be recommended as routine practice; however, in very specific cases it may be justified only after discussion with specialist in microbiology/ infectious diseases and appropriate permissions obtained from the Trust Drugs & Therapeutics group. An example of situation where this off licence use might be considered, would be a severe CDI case (where oral metronidazole is associated with worse clinical outcomes) with concurrent VRE infection or in the context of a VRE outbreak where it would be prudent to restrict oral vancomycin use.

NB. Death certification.21
Doctors have a legal duty to mention CDI on a death certificate if it was part of the sequence of events directly leading to death or contributed in some way

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Provenance

Record: 4731
Objective:

Aims

  • To improve the risk stratified management of Clostridium difficile infection (CDI) in children between 2-16 years of age.

Objectives

  • To provide evidence-based recommendations for appropriate non-antimicrobial management of CDI.
  • To provide evidence-based recommendations for appropriate antimicrobial therapy of CDI.
  • To recommend appropriate dose, route of administration and duration of antimicrobial agents.
  • To set out criteria for referral to specialists.
Clinical condition:

Clostridium difficile infection

Target patient group: Paediatric patients with Clostridium difficile infection
Target professional group(s): Secondary Care Doctors
Pharmacists
Adapted from:

LTHT guideline “Diagnosis and management of Clostridium difficile infection (CDI) in adults (>16 years of age)


Evidence base

1. Schwartz KL, Darwish I, Richardson SE, Mulvey MR, Thampi N. Severe clinical outcome is uncommon in clostridium difficile infection in children: A retrospective cohort study. BMC Pediatr. 2014;14:28

2. Stoesser N, Griffiths D, Fung R, Vaughan A, Crook DW, Dingle K. Re-visiting clostridium difficile in children: Reservoir, victims, both or none? Journal of Infection. 2009;59:S429-S430

3. APA COMMITTEE ON INFECTIOUS DISEASES Clostridium difficile Infection in Infants and Children DOI: 10.1542/peds.2012-2992 Pediatrics 2013;131;196; originally published online December 31, 2012

4. Epidemiology of Clostridium difficile Infection Daryl D. DePestel, David M. Aronoff J Pharm Pract. 2013 October ; 26(5): 464–475. doi:10.1177/0897190013499521.

5. Allen UD, Canadian Paediatric Society, Infectious Diseases and Immunization Committee. Clostridium difficile in paediatric populations. Paediatrics & Child Health. 2014;19(1):43-48.

6. Shim JO. Clostridium difficile in Children: To Treat or Not to Treat? Pediatric Gastroenterology, Hepatology & Nutrition. 2014;17(2):80-84. doi:10.5223/pghn.2014.17.2.80.

7. Schutze, G. E., Willoughby, R. E., Brady, M. T., Byington, C. L., Davies, H. D., Edwards, K. M., & Zaoutis, T. E. (2013). Clostridium difficile infection in infants and children. Pediatrics, 131(1), 196-200.

8. Pai S, Aliyu SH, Enoch DA, Karas JA (2012) Five Years Experience of Clostridium difficile Infection in Children at a UK Tertiary Hospital: Proposed Criteria for Diagnosis and Management. PLoS ONE 7(12): e51728. doi:10.1371/journal.pone.0051728

9. Lamontagne, F., et al., Impact of emergency colectomy on survival of patients with fulminant Clostridium difficile colitis during an epidemic caused by a hypervirulent strain. Ann Surg, 2007. 245(2): p. 267-72.

10. Department_of_Health, Clostridium difficile infection: How to deal with the problem, D.o. Health, Editor. 2008.

11. Lipsett, P.A., et al., Pseudomembranous colitis: a surgical disease? Surgery, 1994. 116(3): p. 491-6.

12. Zar, F.A., et al., A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis, 2007. 45(3): p. 302-7.

13. Wilcox, M.H. and R. Howe, Diarrhoea caused by Clostridium difficile: response time for treatment with metronidazole and vancomycin. J Antimicrob Chemother, 1995. 36(4): p. 673-9.

14. Musher, D.M., et al., Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis, 2005. 40(11): p. 1586-90.

15. Bolton, R.P. and M.A. Culshaw, Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile. Gut, 1986. 27(10): p. 1169-72.

16. NICE. Clostridium difficile infection: fidaxomicin. 2012. http://www.nice.org.uk/advice/esnm1/chapter/Overview

17. Pepin, J., et al., Management and outcomes of a first recurrence of Clostridium difficile-associated disease in Quebec, Canada. Clin Infect Dis, 2006. 42(6): p. 758-64.

18. Wilcox, M.H., Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea. J Antimicrob Chemother, 2004. 53(5): p. 882-4.

19 Stephanie Smeltzer and Ali Hassoun. Successful use of fidaxomicin in recurrent Clostridium difficile infection in a child J. Antimicrob. Chemother. (2013) 68 (7): 1688-1689 doi:10.1093/jac/dkt079

20. Pam Sears, Sheldon L. Kaplan, Marian Michaels, Shawn Flanagan, and Molly O'gorman. LB-8 A Safety and Pharmacokinetic Study of Fidaxomicin in Children with Clostridium difficile-associated diarrhea Open Forum Infect Dis (Fall 2014) 1 (suppl 1): S69 doi:10.1093/ofid/ofu083.08

21. Chief_Medical_Officer, Healthcare Associated Infections and Death Certification. PL CMO (1007)8. 2007.

Evidence levels:

A. Meta-analyses, randomised controlled trials/systematic reviews of RCTs
B. Robust experimental or observational studies
C. Expert consensus.
D. Leeds consensus. (where no national guidance exists or there is wide disagreement with a level C recommendation or where national guidance documents contradict each other)

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Approved By

Improving Antimicrobial Prescribing Group

Document history

LHP version 1.0

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